Orally effective methylphenidate extended release powder and aqueous suspension product

• US 8,287,903 B2
• Filed: 09/26/2011
• Issued: 10/16/2012
• Est. Priority Date: 02/15/2011
• Status: Active Grant

• Current Assignee: Tris Pharma Incorporated
• Original Assignee: Tris Pharma Incorporated
• Inventors: Mehta, Ketan, Tu, Yu-Hsing, Perumal, Ashok
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Tcherkasskaya, Olga V
• Application Number:
  US13/244,706
• Publication Number:
  US 20120207824A1
• Time in Patent Office: 386 Days
• Field of Search: None
• US Class Current: 424/452
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 31/787 containing heterocyclic rings having nitrogen as a ring hetero atom
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

An oral methylphenidate powder which is reconstitutable into a final oral aqueous sustained release formulation containing at least about 50%, or at least about 80% by weight water based on the total weight of the suspension, is provided. The powder is a blend containing a combination of an uncoated methylphenidate-ion exchange resin complex, a barrier coated methylphenidate-ion exchange resin complex-matrix, and a water soluble buffering agent such that upon formed into an aqueous liquid formulation, the formulation has a pH in the range of about 3.5 to about 5, or about 4 to about 4.5. Following administration of a single dose of the oral aqueous methylphenidate suspension, a therapeutically effective amount of methylphenidate is reached in less than one hour and the composition provides a twelve-hour extended release profile.

Claims

1. A methylphenidate aqueous extended release oral suspension consisting of a combination of

(a) a sustained release, cured, water-permeable, water-insoluble, non-ionic, polymeric diffusion barrier coated methylphenidate-ion exchange resin complex—

matrix, wherein the cured diffusion barrier coating comprises about 70 to about 90% polyvinylacetate, about 2.5 to about 15% of a plasticizer, and a stabilizer,

(b) an immediate release methylphenidate component,

(c) at least 50% by weight water based on the total weight of the liquid component of the suspension, and

(d) pharmaceutically acceptable excipients,

wherein said suspension has a pH of about 3.5 to about 5, and said suspension providing a therapeutically effective plasma profile of d-methylphenidate for about 12 hours and a single mean plasma concentration peak for d-methylphenidate.

2. The methylphenidate aqueous extended release oral suspension according to claim 1, wherein said suspension has a pH in the range of about 4 to about 4.5.

3. The methylphenidate aqueous extended release oral suspension according to claim 1, wherein said suspension contains at least about 80% water by weight based on the total weight of the suspension.

4. The methylphenidate aqueous extended release oral suspension according to claim 1 wherein said suspension has a pharmacokinetic profile in which the single mean plasma concentration peak for d-methylphenidate has an area under the curve (AUC)_0-∞

of about 114 ng-hr/mL to about 180 ng-hr/mL, C_max of about 11 ng/mL to about 17 ng/mL, T_max of about 4 hours to about 5.25 hours and T_1/2 of about 5 hours to about 7 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

5. The methylphenidate aqueous extended release oral suspension according to claim 4 wherein said suspension has a pharmacokinetic profile for d-methylphenidate having an AUC_0-∞

of about 143.65 ng-hr/mL, C_max of about 13.61 ng/mL, T_max of about 5 hours and T_1/2 of about 5.65 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

6. The methylphenidate aqueous extended release oral suspension according to claim 1 wherein said suspension has a pharmacokinetic profile in which the single mean plasma concentration peak for d-methylphenidate has an area under the curve (AUC)_0-∞

of about 137.2 to about 214.4 ng-hr/mL, a C_max of about 13.6 to about 21.3 ng/mL, and T_max of about 3 to about 5 hours, following a single oral administration of an aqueous suspension at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.

7. The methylphenidate aqueous extended release oral suspension according to claim 6 wherein said suspension has a pharmacokinetic profile for d-methylphenidate having an AUC_0-∞

of about 171.5 ng-hr/mL, a C_max of about 17.0 ng/mL, and a T_max of about 3.77 hours following a single oral administration of an aqueous liquid suspension at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.

8. The methylphenidate aqueous extended release oral suspension according to claim 1, wherein said methylphenidate is selected from the group consisting of methylphenidate and dexmethylphenidate.

9. An aqueous methylphenidate extended release suspension having a pH in the range of about 4 to about 4.5 comprising at least about 80% water and a combination of (a) a sustained release, cured, water-permeable, water-insoluble, non-ionic, polymeric diffusion barrier coated methylphenidate-ion exchange resin complex-matrix, wherein the cured diffusion barrier coating comprises about 70 to about 90% polyvinylacetate, about 2.5 to about 15% of plasticizer, and a stabilizer, and said methylphenidate-ion exchange resin complex is in a matrix formed by granulating said complex with at least one hydrophilic or hydrophobic polymeric matrix forming component and (b) an immediate release uncoated methylphenidate-ion exchange resin complex, wherein the coated methylphenidate-ion exchange resin complex-matrix of (a) are particulates having an average size range of about 100 microns to about 250 microns, said suspension providing a single mean plasma concentration peak for d-methylphenidate and a therapeutically effective plasma profile of d-methylphenidate for about twelve hours.

10. A methylphenidate extended release powder blend, said extended release powder blend consisting of (i) an immediate release methylphenidate component;

(ii) a cured water-permeable, high tensile strength, water insoluble, non-ionic, sustained release diffusion barrier coating comprising about 70 to about 90% polyvinylacetate polymer, about 2.5 to about 15% of a plasticizer, and a stabilizer over a methylphenidate—

ion exchange resin complex-matrix;

(iii) a water soluble buffering agent which adjusts the pH of an aqueous suspension formed by admixing said extended release powder blend with water to a pH in the range of about 3.5 to about 5; and

(iv) optional pharmaceutical excipients, said powder blend providing a therapeutically effective plasma profile of d-methylphenidate for about 12 hours hours and a single mean plasma concentration peak for d-methylphenidate.

11. The methyphenidate extended release powder blend according to claim 10, wherein the immediate release methylphenidate component is an uncoated methylphenidate-ion exchange resin complex, optionally in a matrix with a hydrophilic or hydrophobic polymeric matrix forming component.

12. The methylphenidate extended release powder blend according to claim 11, wherein the cured barrier coating further comprises a surfactant.

13. The methylphenidate extended release powder blend according to claim 12, wherein the cured barrier coating further comprises about 5 to about 10% of the stabilizer, and about 0.1 to about 1% surfactant.

14. The methylphenidate extended release powder blend according to claim 12, wherein the plasticizer is triacetin and the surfactant is sodium lauryl sulfate.

15. The methylphenidate extended release powder blend according to claim 10, wherein the cured barrier coat is present in an amount which comprises about 20% to about 45% weight gain to the precoated methylphenidate-ion exchange resin complex-matrix.

16. The methylphenidate extended release powder blend according to claim 10, wherein the coated methylphenidate ion exchange resin complex-matrix comprises a hydrophilic polymer in an amount of about 5 to about 20% by weight, based on the weight of the precoated methylphenidate-ion exchange resin complex-matrix.

17. The methylphenidate extended release powder blend according to claim 16, wherein the hydrophilic polymer is polyvinylpyrrolidone.

18. The methylphenidate extended release powder blend according to claim 10, wherein the coated methylphenidate ion exchange resin complex-matrix comprises a hydrophobic polymer or co-polymer in an amount of about 5 to about 20% by weight, based on the weight of the precoated methylphenidate-ion exchange resin complex-matrix.

19. The methylphenidate extended release powder blend according to claim 10, wherein the extended release powder blend contains about 10 to about 30 parts by weight methylphenidate as provided in the immediate release component provided in (i) and about 70 to about 90 parts by weight methylphenidate as provided in the sustained release component provided in (ii), based upon the total weight of methylphenidate in the extended release powder blend.

20. The methylphenidate extended release powder blend according to claim 10, wherein said methylphenidate extended release powder blend further comprises water-soluble diluent granules which contain the buffering agent.

21. The methylphenidate extended release powder blend according to claim 20, wherein said buffering agent is selected from the group consisting of one or more of a pharmaceutically acceptable acid selected from the group consisting of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, or a mixture of said pharmaceutically acceptable acid or salt.

22. The methylphenidate extended release powder blend according to claim 21, wherein said buffering agent is a mixture of sodium citrate and anhydrous citric acid.

23. The methylphenidate extended release powder blend according to claim 21, wherein the diluent granules further comprise one or more of a surfactant, a sweetener, and a preservative.

24. The methylphenidate extended release powder blend according to claim 23, wherein the surfactant in the diluent granules comprises a poloxamer.

25. The methylphenidate extended release powder blend according to claim 10, wherein said methylphenidate is selected from the group consisting of methylphenidate and dexmethylphenidate.

26. A solid dose unit in the form of a tablet or capsule comprising a methylphenidate extended release powder blend, said extended release powder blend comprising (i) an immediate release methylphenidate component and (ii) a cured, water-permeable, high tensile strength, water insoluble, non-ionic sustained release polymeric diffusion barrier coated methylphenidate-ion exchange resin complex-matrix, said cured diffusion barrier coating comprising about 70 to about 90% polyvinylacetate, about 2.5 to about 15% of a plasticizer, and a stabilizer, and being present in an amount of about 20% to about 45% weight gain to the methylphenidate-ion exchange resin complex-matrix based the weight of the matrix pre-coating, and wherein (i) and (ii) are provided in a ratio of about 10 to about 30 parts methylphenidate as provided in the immediate release component (i) to about 70 to about 90 parts by weight methylphenidate as provided in sustained release (ii), based on the total weight of methylphenidate in the extended release powder blend, said solid dose unit providing a single mean plasma concentration peak for d-methylphenidate and a therapeutically effective plasma profile of d-methylphenidate for about twelve hours.

27. The solid dose unit according to claim 26 having a pharmacokinetic profile in which the single mean plasma concentration for d-methylphenidate has an area under the curve (AUC)_0-∞

of about 114 ng-hr/mL to about 180 ng-hr/mL, C_max of about 11 ng/mL to about 17 ng/mL, T_max of about 4 hours to about 5.25 hours and a T_1/2 of about 5 hours to about 7 hours following a single oral administration at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

28. The solid dose unit according to claim 27 having a pharmacokinetic profile for d-methylphenidate having an AUC_0-∞

of about 143.65 ng-hr/mL, C_max of about 13.61 ng/mL, T_max of about 5 hours and T_1/2 of about 5.65 hours following a single oral administration at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

29. The solid dose unit according to claim 26 having a pharmacokinetic profile for d-methylphenidate having an area under the curve (AUC)_0-∞

of about 137.2 to about 214.4 ng-hr/mL, a C_max of about 13.6 to about 21.3 ng/mL, and T_max of about 3 to about 5 hours, following a single oral administration at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.

30. The solid dose unit according to claim 29 having a pharmacokinetic profile in which methylphenidate has an AUC_0-∞

of about 171.5 ng-hr/mL, a C_max of about 17.0 ng/mL, and a T_max of about 3.77 hours following a single oral administration of an aqueous liquid suspension at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.